A DEFECT IN SKELETAL-MUSCLE SODIUM-CHANNEL DEACTIVATION EXACERBATES HYPEREXCITABILITY IN HUMAN PARAMYOTONIA-CONGENITA

1. Paramyotonia congenita (PC) is a human hereditary disorder wherein missense mutations in the skeletal muscle sodium channel lead to cold- exacerbated muscle hyperexcitability. The most common site for PC muta tions is the outermost arginine of domain IV segment 4 (human R1448, r at R1441). 2. We examined the rat homologues of two PC mutants with ch anges at this site: R1441P and R1441C. The R-->P mutation leads to the most clinically severe form of the disease. Since PC has so far been attributed to defects in fast inactivation, we expected the R-->P subs titution to have a more dramatic effect on fast inactivation than R--> C. Both mutants (R1441P and R1441C), however, had identical rates and voltage dependence of fast inactivation and activation. 3. R1441P and R1441C also had slowed deactivation, compared with wild-type, raising the possibility that slowed deactivation, in combination with defectiv e fast inactivation, might be a contributing cause of paramyotonia con genita. Furthermore, deactivation was slower in R1441P than in R1441C, suggesting that the worse phenotype of the human R-->P mutation is du e to a greater effect on deactivation, and supporting our hypothesis t hat slowed sodium channel deactivation contributes to paramyotonia con genita. 4. We show that the downstroke of the muscle action potential produced a sodium tail current, and thus slowed deactivation opposes r epolarization and therefore leads to hyperexcitability. Hyperexcitabil ity due to slowed deactivation, which has previously been overlooked, also predicts the temperature sensitivity of PC, which has otherwise n ot been adequately explained.